High rates of reactivation of varicella zoster virus (VZV) associated with bortezomib (VELCADE) when given pre and post high dose chemotherapy (HDCT)

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We evaluated the tolerability and efficacy of the proteasome inhibitor bortezomib administered to multiple myeloma (MM) patients both prior to, and as consolidation therapy following HDCT, in a prospective pilot study. Patients received 2 cycles of bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of every 21 days, prior to stem cell collection and melphalan 200mg/m², followed by six cycles of consolidation bortezomib 1.3 mg/m² given once weekly for 4 of every 5 weeks, 90–120 days following transplantation. Of 40 enrolled patients, 33 have received at least one post transplantation cycle of consolidation bortezomib. Patient and disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0–3.6) (n = 33), day 1 cycle 4 was 0.1 (range 0–2.1) (n = 23), and at end of study was 0.35 (range 0–3.4) (n = 20). With a median follow up of 14 months, disease progression has occurred in 5 patients with 1 death. Fourteen patients (42%) experienced reactivation of VZV, 2 patients had human herpes virus 6 reactivation, and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count at the onset of viral reactivation was 1336/mcl (range = 600–4800/mcl). A significant difference was seen in the mean CD8 count just prior to transplantation between those patients with viral reactivation (243, range 77–685) and the rest of the study population (392, range 87–1339) (P = .03). The median time from enrollment to VZV reactivation was 189 days (range 25–375). Ten patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 (64%) had grade 1/2 neuropathy and 1 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 patients (9%), necessitating dose reduction (1 patient) or discontinuation of therapy (2 patients). No grade 3/4 thrombocytopenia or neutropenia was observed with consolidation bortezomib. We conclude that bortezomib when administered pre- and post HDCT in MM patients results in a very high rate of viral reactivation. This finding may be explained by a decrease in circulating CD8 T cells and has implications for future clinical trials of bortezomib in this setting.